ABSTRACT: Tactile sensitivity of detecting gentle mechanical stimuli or touch is critically important in life but can be impaired to result in reduction/loss of tactile sensitivity (numbness) under pathological conditions. Numbness is the earliest and most common symptom of chemotherapy-induced peripheral neuropathy (CIPN) that negatively impacts quality of life in cancer patients, and it is a dose-limiting factor of chemotherapy. Numbness of CIPN is poorly treated and its underlying mechanism understudied. This lack of knowledge prevents development of effective management for numbness CIPN. ? A Merkel disc is a main type of tactile end organ located in touch sensitive spots throughout the body but most abundant at the human fingertips and whisker hair follicles of all non-primate mammals. A Merkel disc consists of a Merkel cell and an A?-afferent ending to form a synapse-like structure. We and others have recently discovered that tactile stimuli to Merkel discs are largely transduced in Merkel cells by Piezo2 channels, which drive most A?-afferent impulses and behavioral tactile responses. More recently, we have further identified that Merkel discs in whisker hair follicles are serotonergic synapses, and serotonin is released from Merkel cells in response to tactile stimuli to subsequently drive A?-afferent impulses and behavioral tactile responses. ? In this renewal application, our new focuses are to study how tactile sensitivity at Merkel discs is modulated and whether the tactile sensitivity can be impaired by chemotherapy drugs to account for the numbness aspect of CINP. ? We propose to use whisker hair follicle preparation to address these questions with 3 specific aims: Aim 1) Elucidate mechanisms underlying the modulation of Merkel disc tactile sensitivity. This Aim will focus on whether serotonin transporters play a key role in regulating Merkel disc serotonergic transmission and Merkel disc tactile sensitivity. Aim 2: Determine whether and how chemotherapy drugs impair Merkel disc tactile sensitivity. This Aim will measure changes of serotonergic transmission and Merkel disc tactile sensitivity following chemotherapy drug treatment, and identify pre- and postsynaptic molecules at Merkel discs that are targeted by chemotherapy drugs to result in the impairment of Merkel disc tactile sensitivity. Aim 3: Determine whether targeting Merkel discs by chemotherapy drugs leads to impairment of behavioral tactile responses. This Aim will determine whether chemotherapy drugs can impair whisker tactile behavioral responses via suppressing Merkel disc serotonergic transmission, and whether potentiation of Merkel disc serotonergic transmission by pharmacologically manipulating serotonin transporters can rescue the impaired whisker tactile behavioral responses. ? Completion of the 3 Aims will fill a scientific gap about tactile sensitivity of mammals, elucidate novel mechanisms underlying numbness aspect of CIPN, and identify potential therapeutic targets for rescuing impaired tactile sensitivity.